PROJECT SUMMARY Dr. Susan Bullman is a multi-disciplinary postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-Farber Cancer Institute and Broad Institute. In alignment with the NCI mission, her long- term goal is to lead an independent research group studying the role of tumor microbiota in initiation, progression, and treatment of human gastrointestinal cancers to ultimately reduce cancer-associated mortality and suffering. Unbiased genomic analyses have revealed an enrichment of Fusobacterium nucleatum, in human colorectal cancers (CRC) relative to non-cancerous colorectal tissues. Exogenous F. nucleatum infection in animal and cellular models has supported its cancer-promoting role. Additionally, patients with CRC that harbor high levels of Fusobacterium in their tumors show worse survival, suggesting that targeting Fusobacterium may provide a novel therapeutic route, potentiate the effects of chemotherapies, and improve disease prognosis. Stemming from preliminary data, this proposal will test the hypotheses that (A) Fusobacterium can be used as a novel therapeutic target in colonized tumors: inhibition of Fusobacterium growth in Fusobacterium- positive patient derived colorectal cancer xenografts will significantly reduce cancer cell proliferation and tumor growth (Aim-1), (B) F. nucleatum strains have varying pro-carcinogenic capabilities and analysis of tumor ecology relating to Fusobacterium?s localization, co-occurring microbiota, and host gene expression in CRC will identify ?high-risk? signatures predictive of metastasis (Aim-2), and finally, (C) F. nucleatum, one of the most abundant species in CRC tumors, directly modulates/metabolizes routine cancer chemotherapeutics and that this drug modification contributes to diminished efficacy and response in colon cancers (Aim-3). Dr. Bullmans K99 phase will be performed under the primary mentorship of Dr. Meyerson: a leader in cancer genomics and co-discovered the enrichment of Fusobacterium in colorectal adenocarcinomas. Additionally, an advisory committee consisting of Drs. Bass, Dewhirst, Ogino and Schreiber will monitor her scientific progress, career development, and guide her transition to a tenure-track faculty position. This training period will allow Dr. Bullman to gain experience in pre-clinical cancer treatment models, in-situ hybridization approaches, and analytical chemistry. In the mentored K99 phase Dr. Bullman will focus on determining ?what Fusobacterium can do? in these human tumors, to maximize the translational impact of her research and provide the foundation for transition to the independent R00 phase, with a focus on more mechanistic studies addressing ?how Fusobacterium is doing it?. The logical and methodical experiments proposed by Dr. Bullman will provide novel insights into the contribution of Fusobacterium to CRC and support her future independent research.